Pre-Exposure Prophylaxis (PrEP) 1° Prevention of HIV in At-Risk … · 2012-07-03 · Final...

Pre-Exposure Prophylaxis (PrEP)

1° Prevention of HIV in At-Risk Women:

Coming of Age

Aaron Kofman, BA, MD ’14

Eli Y. Adashi, MD, MS, CPE, FACOG

BRIGHT Series June 12, 2012

Women and the HIV Epidemic

Global Indicators

2010

Global Indicator1 Datum2

New HIV Infections a Year 1,100,000(41% of Total)

Annual HIV-related Deaths 730,000(41% of Total)

HIV(+) Women Receiving ARVs (% in Need) 53%

1LMICs 2WHO/UNAIDS/UNICEF: GLOBAL HIV/AIDS RESPONSE, 2011


Women Living with HIV 17,000,000

Women Living with HIV (% of Total Global Cohort) 50%

Women Living with HIV (% of Total SSA Cohort)3 59%

1LMICs 2WHO/UNAIDS/UNICEF: GLOBAL HIV/AIDS RESPONSE, 20113SSA=Sub-Saharan Africa


Young Women Living with HIV3 3,200,000

Young Women Living with HIV (% of Young Global Cohort) 64%

Young Women Living with HIV (% of Young SSA Cohort)4 71%

1LMICs 2WHO/UNAIDS/UNICEF: GLOBAL HIV/AIDS RESPONSE, 20113Young Women=15-24 Years Old4SSA=Sub-Saharan Africa

Trends: Women & HIV

• New HIV infections are on the decline

• Dying of HIV-related causes is on the decline

• Living with HIV has stabilized at 50% of total

• ART coverage of eligible women has increased to 53%

PrEP in Women

Addressing Unique Challenges

• Inability to negotiate safe sex due to gender

inequity and harmful gender norms:

Abusive and violent relationships

Transactional survival sex

Cross-generational (age-disparate) sex

Absent social or economic power

• Unknowns of casual relationships:

Improbability of abstinence & monogamy

Unreliability of condom use & male circumcision

• Increased risk of transmission:

Twice as vulnerable as men

Twice as vulnerable during pregnancy

PrEP in Women

Going Beyond Prevention

Prevention Through Empowerment

“…little attention has been given to barriers to HIV

transmission that depend on the woman and are under

her control…including the possibility of a topical

virucide that might block transmission through the

vaginal route.”Am J Public Health 1990;80:460-462

The History of PrEP

1990-2007Non-specific Topical Antivirals

Class Agent

Trials

(#) Outcome

Surfactants

Nonoxynol-9

4 NegativeSAVVY (C31G)

Polymers

Cellulose Sulfate

8 Negative

Carraguard

PRO2000

BufferGel

1990-2007Non-specific Topical Antivirals

2007-2012Specific Antiretroviral Agents

(Topical & Systemic)

Tenofovir Disoproxyl Fumarate (TDF)

Emtricitabine (FTC)

Dapivirine (TMC120)

Maraviroc

The History of PrEP

Early Successes

Trial Intervention

CAPRISA 004 Peri-coital Vaginal TDF Gel

Partners PrEP Daily Oral TDF or TDF/FTC Tablets

TDF2 Daily Oral TDF/FTC Tablets

CAPRISA 004

Abdool Karim Q. et al. Science 329: 1168-1174, 2010

CAPRISA 004

Phase IIb, Two Arm, Double-Blind RPCT

Completed March 2010

Variable Datum

Intervention Pericoital Vaginal TDF Gel (1%)

Pericoital Vaginal Placebo Gel

Participants 889 HIV(-) Heterosexual Women (at high risk) Ages 18 to 40

1° Outcome HIV Seroconversion

Adherence

MeasureReturned Used Applicators

CAPRISA 004

Phase IIb, Two Arm, Double-Blind RPCT

Completed March 2010

Variable Datum

Intervention Peri-coital Vaginal TDF Gel (1%)

Peri-coital Vaginal Placebo Gel

Participants 889 HIV(-) Heterosexual Women Ages 18 to 40


ResultsLow (<50%) adherence:

Intermediate (50-80%) adherence:

High (>80%) adherence:

28% protection38% protection54% protection

Lessons PrEP is accomplishable (proof of concept)

PrEP efficacy is adherence-dependent

39% risk reduction is not good enough

TDF2

Key Facts: http://www.cdc.gov/hiv/prep/pdf/TDF2factsheet.pdf

http://www.cdc.gov/hiv/prep/pdf/TDF2factsheet.pdf

TDF2

Phase IIb, Two Armed, Double-Blind RPCT

Completed July 2011

Metric Datum

InterventionDaily Oral TDF/FTC Tablets

Daily Oral Placebo Tablets

Participants 1219 HIV (-) Heterosexual Women Ages 18 to 39


TDF2

Phase IIb, Two Armed, Double-Blind RPCT

Completed July 2011

Metric Datum



Participants 1219 HIV (-) Heterosexual Women Ages 18 to 39


Results TDF/FTC afforded 76% protection to women

Adherence Overall Adherence Rate (Residual Pill Count): 84%

Partners PrEP

Press Release: http://www.avac.org/ht/a/GetDocumentAction/i/35459

http://www.avac.org/ht/a/GetDocumentAction/i/35459

Partners PrEP

Phase III, Three Arm, Double-Blind RPCT

Completed July 2011

Metric Datum

Intervention

Daily Oral TDF Tablets to HIV (-) Partner

Daily Oral TDF/FTC Tablets to HIV (-) Partner

Daily Placebo Tablets to HIV (-) Partner

Participants 4,758 stable heterosexual HIV-discordant couples

1° Outcome Seroconversion of HIV (-) Partner

Partners PrEP

Phase III, Three Arm, Double-Blind RPCT

Completed July 2011

Metric Datum

Intervention

Daily Oral TDF Tablets to HIV (-) Partner

Daily Oral TDF/FTC Tablets to HIV (-) Partner

Daily Oral Placebo Tablets to HIV (-) Partner

Participants 4,758 Stable Heterosexual HIV-discordant Couples

1° Outcome Seroconversion of HIV (-) Partner

ResultsTDF afforded 68% protection to women partners

TDF/FTC afforded 62% protection to women partners


On the Importance of “Couple Trials”The sub-Saharan Example

75% of adults (20–49) are in cohabiting unions

≤50% of cohabiting HIV (+) adults have an HIV (-) partner

Women are as likely as men to be the index partner

Serodiscordant couples are likely HIV status agnostic

New infections are on the rise in serodiscordant couples

The History of PrEP

Recent Failures

Trial Intervention

FEM PrEP Daily Oral TDF/FTC Tablets

VOICE Daily Oral TDF Tablets or Vaginal TDF Gel

FEM-PrEP

Press Release: http://www.cdc.gov/hiv/prep/femprep.htm

http://www.cdc.gov/hiv/prep/femprep.htm

FEM PrEP

Phase III, Two Arm, Double-Blind RPCT

Variable Datum



Participants 1951 HIV(-) Heterosexual Women (at high risk) Ages 18 to 35


FEM PrEP

Phase III, Two Arm, Double-Blind RPCT

Variable Datum



Participants 1951 HIV(-), Heterosexual, 18 to 35 Year-Old Women


Results Trial halted 4/18/11 by the IDMC* for futility


*Independent Data Monitoring Committee

Why did FEM-PrEP Fail?

The FEM PrEP trial failed, at least in part,

due to poor product adherence.

Post Hoc Analysis

Only 26% of the women in the treatment arm

displayed detectable serum levels of TDF at

the last visit prior to seroconversion.

Possible Drivers of Poor Adherence

• Youthful perception of invincibility

• Duration of the study (“Study Fatigue”)

• Failure to refill drug supplies (i.e. skipped visits)

• Lingering stigma of HIV

• Presumed assignment to the placebo arm

• Pill sharing between trial participants

VOICE*

Projected Results: Late 2012

*VOICE=Vaginal and Oral Interventions to Control the Epidemic

VOICE

Phase IIb, Five Arm, Double-Blind RPCT

Variable Datum

Intervention

Daily Oral TDF Tablets

Daily Oral TDF/FTC Tablets

Daily Vaginal TDF Gel

Daily Placebo Tablets or Placebo Vaginal Gel

Participants 5029 HIV(-) Heterosexual Women Ages 18 to 45


Results

Oral TDF arm halted by the DSMB* on 9/16/11 for futility

Vaginal TDF arm halted by the DSMB* on 11/17/11 for futility

Post hoc analysis is pending

Oral TDF/FTC arm is ongoing

*Data and Safety Monitoring Board

Going Forward

Current and Upcoming Phase III PrEP Trials

Results are Expected in 2014

Trial Intervention

FACTS 001 Peri-coital TDF Vaginal Gel

ASPIRE Long-Acting Dapivirine-Releasing Vaginal Ring

IPM 027 Long-Acting Dapivirine-Releasing Vaginal Ring

Regulatory Approval

Truvada® tablets be approved for PrEP in:

Men having sex with men

HIV (-) negative partners in serodiscordant couples

Others at risk due to sexual activity

Tenofovir vaginal gel or oral tablets are not

candidates for approval as PrEP at this time

FDA Advisory Committee: May 10, 2012

Final ThoughtsThe promise of PrEP for the 1° prevention of HIV in

at-risk women is still best viewed as work in

progress

Regulatory approval is likely to be granted to

Truvada® tablets as PrEP in serodiscordant couples

and in women deemed to be at high risk.

Regulatory approval of the Tenofovir Vaginal gel as

PrEP is contingent on the outcome of FACTS 001

and thus is not anticipated until 2015 at the earliest.

Final ThoughtsStable serodiscordant couples may be better served

by treatment of the HIV (+) partner (96%

protection) than by PrEP of the HIV (-) partner

(73% protection)

PrEP effectiveness may be well served by:

Favoring multi-agent paradigms capable of targeting

several especially earlier phases of the HIV life cycle

Focusing on user-independent PrEP strategies i.e.

vaginal rings, injectables, implantables, and

transdermal patches

Conclusions

The effectiveness of long-

acting reversible

contraception (IUD or

Implants) is superior to

that of contraceptive pills,

patch, or ring.

New Engl J Med

366:1998-2007, 2012

Residual All Important Matters

Impact of PrEP on disease burden

Optimal population target (s)

Implementational costs

Implementational Logistics

Cost-effectiveness

Prioritization by donors/payers

Risk Compensation

Resistance development

Drug safety

The End

Pre-Exposure Prophylaxis (PrEP) 1° Prevention of HIV in At-Risk … · 2012-07-03 · Final...

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